Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press HIV-1 Antiretroviral Drug Therapy Eric J. Arts1 and Daria J. Hazuda2 1Ugandan CFAR Laboratories, Division of Infectious Diseases, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106 2Merck Research Laboratories, West Point, Pennsylvania 19486 Correspondence: [email protected]; [email protected] The most significant advance in the medical management of HIV-1 infection has been the treatment of patients with antiviral drugs, which can suppress HIV-1 replication to undetect- able levels. The discovery of HIV-1 as the causative agent of AIDS together with an ever- increasing understanding of the virus replication cycle have been instrumental in this effort by providing researchers with the knowledge and tools required to prosecute drug discovery efforts focused on targeted inhibition with specific pharmacological agents. To date, an arsenal of 24 Food and Drug Administration (FDA)-approved drugs are available for treatment of HIV-1 infections. These drugs are distributed into six distinct classes based on their molecular mechanism and resistance profiles: (1) nucleoside-analog reverse tran- scriptase inhibitors (NNRTIs), (2) non–nucleoside reverse transcriptase inhibitors (NNRTIs), (3) integrase inhibitors, (4) protease inhibitors (PIs), (5) fusion inhibitors, and (6) coreceptor antagonists. In this article, we will review the basic principles of antiretroviral drug therapy, the mode of drug action, and the factors leading to treatment failure (i.e., drug resistance). BASIC PRINCIPLES OF ANTIRETROVIRAL development and approval for human use is THERAPY described in Figure 1. Since the first HIV-1 specific antiviral drugs efore 1996, few antiretroviral treatment were given as monotherapy in the early 1990s, Boptions for HIV-1 infection existed. The the standard of HIV-1 care evolved to include clinical management of HIV-1 largely consisted the administration of a cocktail or combination www.perspectivesinmedicine.org of prophylaxis against common opportunistic of antiretroviral agents (ARVs). The advent of pathogens and managing AIDS-related ill- combination therapy, also known as HAART, nesses. The treatment of HIV-1 infection was for the treatment of HIV-1 infection was semi- revolutionized in the mid-1990s by the devel- nal in reducing the morbidity and mortality opment of inhibitors of the reverse trans- associated with HIV-1 infection and AIDS criptase and protease, two of three essential (Collier et al. 1996; D’Aquila et al. 1996; Stas- enzymes of HIV-1, and the introduction of zewski et al. 1996). Combination antiretroviral drug regimens that combined these agents to therapy dramatically suppresses viral replica- enhance the overall efficacy and durability tion and reduces the plasma HIV-1 viral load of therapy. A timeline of antiretroviral drug (vLoad) to below the limits of detection of the Editors: Frederic D. Bushman, Gary J. Nabel, and Ronald Swanstrom Additional Perspectives on HIV available at www.perspectivesinmedicine.org Copyright # 2012 Cold Spring Harbor Laboratory Press; all rights reserved. Advanced Online Article. Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a007161 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ E.J. Arts and D.J. Hazuda on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press Norvir Ritonavir Abbott Pl 1996 Viramune Nevirapine Sustiva Bl Efavirenz NNRTI BMS 1996 Truvada Pl Tenofovir+ Atripla Crixiva 1998 emtricitabine Tenofovir+ Ziagen Indinavir Gilead emtricitabine+ Abacavir Merck NRTIs efavirenz GSK Trizivir Pl 2004 Gilead and BMS NRTI Abacavir+ 1996 NRTIs + NNRTI 1998 zidovudine+ Lexiva www.perspectivesinmedicine.org ANTIRETROVIRALS 2006 Eipivir Viracept lamivudine Fosamprenavir GSK Lamivudine Nelfinavir GSK Reyata Prezista Pl GSK Pflzer NRTIs Atazanavir Darunavir 2004 NRTI Pl 2000 BMS Tibotec/J&J 1995 1997 Agenerase Pl 2nd-gen. Pl Trade name Fortovase/Invirase Combivir Amprenavir Viread 2003 2006 HIVID Saquinavir Zidovudine+ GSK Tenofovir Emtriva Isentress Company Zalcitabine Roche lamivudine PI Gilead Emtricitabine Raltegravir Drug class Roche Generic name (common abbreviation) NRTI GSK 1999 (discont. 2004) NRTI Gilead Merck NRTI 1995 NRTIs 2001 Pl INI Year of FDA approval 1992 (discont. 2006) 1997 2007 Kaletra 2003 Aptivus Retrovir Videx Zerit Rescriptor (with ritonavir) Fuzeon Selzentry Tipranavir Zidovudine Didanosine Stavudine Delavirdine Lopinavir Enfuvirtide Maraviroc Bl GSK BMS BMS Pflzer Abbott Roche Pfizer Pl NRTI NRTI NRTI NNRTI Pl entry/gp41 Entry/CCR5 2005 1987 1991 1994 1997 2000 2003 2007 1969 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 Ten yearsno 2011 Monotherapy First Triple drug combination (HAART) antiviral approval Dual therapy antiviral – 2 Symmetrel Boceprevir Herpex, Acivirax, Zovirax, Aciclovir, Cytovene, Cymevene, Vitrasert Flumadine Tamiflu Baraclude Famvir Amantadine Merck and Zovir Gancyclovir Rimantadine Oseltamivir Entecavir Famciclovir Multiple pharmaceutical and generic Hepatitis C virus Acyclovir (ACV) Roche Forest Pharmaceuticals Gilead/Roche BMS Novartis NS3 PI companies Multiple pharmaceutical and generic CMV Influenza A virus Influenza A and B virus Hepatitis B virus VZV, HSV-2 Influenza A and B Filed 2010 companies TK/DNA pol inhibitor blocks the M2 ion channel Sialic acid analog/neurominidase NRTI blocks the M2 ion channel TK/DNA pol inhibitor – HSV-1, HSV-2, VZV, EBV, CMV 1989 1994 inhibitor 2005 1969 Foscavir Vistide 2007 Telaprevir TK/DNA pol inhibitor 1999 Foscarnet Codofovir Vertex 1982 Astra Zeneca HCV Advanced Online Article. Cite this article as Copegus, Rebetol, Ribasphere, Vilona, Gilead Biosciences/Pfizer Relenza NS3 PI and Virazole HSV-1, HSV-2, CMV Cytomegalovirus (CMV) in AIDS Zanamivir Filed 2010 Ribavirin DNA polymerase inhibitor patients GSK Multiple pharmaceutical companies 1991 TK/DNA pol inhibitor Influenza A and B virus RSV, HCV 1996 Sialic acid analog/neurominidase Mechanism unknown/possible inhibitor Valtrex ribonucleoside inhibitor 1999 Trade name Valacyclovir 1980 (RSV)/1998 (HCV) GSK Company HSV-1, HSV-2, VZV, EBV, CMV Virus target TK/DNA pol inhibitor Generic name (common abbreviation) 1996 Drug class/mechanism Year of FDA approval ANTIVIRALS Cold Spring Harb Perspect Med Timeline for FDA approval for current antiviral and antiretroviral drugs. doi: 10.1101 Figure 1. / cshperspect.a007161 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 2, 2021 - Published by Cold Spring Harbor Laboratory Press HIV-1 Antiretroviral Drug Therapy most sensitive clinical assays (,50 RNA copies/ capacity or viral fitness to a similar degree. mL) resulting in a significant reconstitution Trial and error with early antiretroviral agents of the immune system (Autran et al. 1997; Ko- helped to establish the basic principles for manduri et al. 1998; Lederman et al. 1998;) effective drug combinations in HAART. Since as measured by an increase in circulating these early days, therapies have evolved, with CD4þ T-lymphocytes. Importantly, combina- the introduction of newer drugs with greater tion therapy using three antiretroviral agents potency and higher barriers to the development directed against at least two distinct molecular of resistance. Moreover, some antiretroviral targets is the underlying basis for forestalling agents have been shown to select for mutations the evolution drug resistance. which are either incompatible with or engender In an untreated individual, on average there hypersensitivity to other antiretroviral drugs, are 104 –105 or more HIV-1 particles per mL of suggesting certain ARVs may offer an advantage plasma, which turn over at a rate of 1010/d with respect to resistance barrier when used in (Ho et al. 1995; Wei et al. 1995; Perelson et al. the context of specific combinations (Larder 1996). Owing to the error-prone reverse tran- et al. 1995; Kempf et al. 1997; Hsu et al. 1998). scription process, it is estimated that one muta- Therefore, whether HIV-1 treatment can be tion is introduced for every 1000–10,000 simplified to two or even one potent drug(s) nucleotides synthesized (Mansky and Temin remains an open question that can only be 1995; O’Neil et al. 2002; Abram et al. 2010). answered with future clinical studies. As the HIV-1 genome is 10,000 nucleotides In 2010, HIV-1 treatment guidelines in the in length, one to 10 mutations may be generated United States and European Union recommend in each viral genome with every replication the initiation of HAART with three fully active cycle. With this enormous potential for generat- antiretroviral agents when CD4 cells in periph- ing genetic diversity, HIV-1 variants with eral blood decline to 350 per cubic mm, a stage reduced susceptibility to any one or two drugs at which viral levels can often reach 10,000– will often preexist in the viral quasispecies 100,000 copies per mL (as measured by RNA before initiating therapy (Coffin 1995). The in the blood) (see http://aidsinfo.nih.gov/ success of HAART results in part from using Guidelines/). With proper adherence, HAART drug combinations that decrease the probability can suppress viral replication for decades, of selecting virus clones (from an intrapatient dramatically increasing the life expectancy of HIV-1 population) bearing multiple mutations the HIV-infected individual. However, HAART and conferring